Current cell therapies for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged by the immune system. Although standard treatment options such as hydroxychloroquine (HCQ), glucocorticoids (GCs), and other immunosuppressive or immune-modulating agents can help to manage symptoms, they do not offer a cure. Hence, there is an urgent need for the development of novel drugs and therapies. In recent decades, cell therapies have been used for the treatment of SLE with encouraging results. Hematopoietic stem cell transplantation, mesenchymal stem cells, regulatory T (Treg) cell, natural killer cells, and chimeric antigen receptor T (CAR T) cells are advanced cell therapies which have been developed and evaluated in clinical trials in humans. In clinical application, each of these approaches has shown advantages and disadvantages. In addition, further studies are necessary to conclusively establish the safety and efficacy of these therapies. This review provides a summary of recent clinical trials investigating cell therapies for SLE treatment, along with a discussion on the potential of other cell-based therapies. The factors influencing the selection of common cell therapies for individual patients are also highlighted.

Clinical Study of Mesenchymal Stem/Stromal Cell Therapy for the Treatment of Frailty: A Proposed Experimental Design for Therapeutic and Mechanistic Investigation.

Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in older people, is an emerging problem worldwide with major implications for clinical practice and public health. Recent preclinical and clinical studies have supported the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. Comprehensive study is needed to assess the interrelationship between the condition of frailty and the effects of MSC-based therapy. This randomized controlled phase I/II trial aims to investigate the safety and potential therapeutic efficacy of the allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with the standard treatment for frailty in Vietnam. Moreover, this study describes the rationales, study designs, methodologies, and analytical strategies currently employed in stem cell research and clinical studies. The primary outcome measures will include the incidences of prespecified administration-associated adverse events and serious adverse events. The potential efficacy will be evaluated based on improvements in frailty conditions (including those determined through a physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient plasma). This clinical trial and stem cell analysis associated with patient sampling at different time points aim to identify and characterize the potential effects of UC-MSCs on improving frailty based on the stem cell quality, cytokine/growth factor secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient CD3+ cells providing fundamental knowledge for designing and implementing research strategies in future studies. Clinical Trials Registration Number: NCT04919135.

Epromoters function as a hub to recruit key transcription factors required for the inflammatory response.

Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response.

Integration of high-throughput reporter assays identify a critical enhancer of the Ikzf1 gene.

The Ikzf1 locus encodes the lymphoid specific transcription factor Ikaros, which plays an essential role in both T and B cell differentiation, while deregulation or mutation of IKZF1/Ikzf1 is involved in leukemia. Tissue-specific and cell identity genes are usually associated with clusters of enhancers, also called super-enhancers, which are believed to ensure proper regulation of gene expression throughout cell development and differentiation. Several potential regulatory regions have been identified in close proximity of Ikzf1, however, the full extent of the regulatory landscape of the Ikzf1 locus is not yet established. In this study, we combined epigenomics and transcription factor binding along with high-throughput enhancer assay and 4C-seq to prioritize an enhancer element located 120 kb upstream of the Ikzf1 gene. We found that deletion of the E120 enhancer resulted in a significant reduction of Ikzf1 mRNA. However, the epigenetic landscape and 3D topology of the locus were only slightly affected, highlighting the complexity of the regulatory landscape regulating the Ikzf1 locus.

A critical regulator of Bcl2 revealed by systematic transcript discovery of lncRNAs associated with T-cell differentiation.

Normal T-cell differentiation requires a complex regulatory network which supports a series of maturation steps, including lineage commitment, T-cell receptor (TCR) gene rearrangement, and thymic positive and negative selection. However, the underlying molecular mechanisms are difficult to assess due to limited T-cell models. Here we explore the use of the pro-T-cell line P5424 to study early T-cell differentiation. Stimulation of P5424 cells by the calcium ionophore ionomycin together with PMA resulted in gene regulation of T-cell differentiation and activation markers, partially mimicking the CD4-CD8- double negative (DN) to double positive (DP) transition and some aspects of subsequent T-cell maturation and activation. Global analysis of gene expression, along with kinetic experiments, revealed a significant association between the dynamic expression of coding genes and neighbor lncRNAs including many newly-discovered transcripts, thus suggesting potential co-regulation. CRISPR/Cas9-mediated genetic deletion of Robnr, an inducible lncRNA located downstream of the anti-apoptotic gene Bcl2, demonstrated a critical role of the Robnr locus in the induction of Bcl2. Thus, the pro-T-cell line P5424 is a powerful model system to characterize regulatory networks involved in early T-cell differentiation and maturation.

Annotating Diseases Using Human Phenotype Ontology Improves Prediction of Disease-Associated Long Non-coding RNAs.

Recently, many long non-coding RNAs (lncRNAs) have been identified and their biological function has been characterized; however, our understanding of their underlying molecular mechanisms related to disease is still limited. To overcome the limitation in experimentally identifying disease-lncRNA associations, computational methods have been proposed as a powerful tool to predict such associations. These methods are usually based on the similarities between diseases or lncRNAs since it was reported that similar diseases are associated with functionally similar lncRNAs. Therefore, prediction performance is highly dependent on how well the similarities can be captured. Previous studies have calculated the similarity between two diseases by mapping exactly each disease to a single Disease Ontology (DO) term, and then use a semantic similarity measure to calculate the similarity between them. However, the problem of this approach is that a disease can be described by more than one DO terms. Until now, there is no annotation database of DO terms for diseases except for genes. In contrast, Human Phenotype Ontology (HPO) is designed to fully annotate human disease phenotypes. Therefore, in this study, we constructed disease similarity networks/matrices using HPO instead of DO. Then, we used these networks/matrices as inputs of two representative machine learning-based and network-based ranking algorithms, that is, regularized least square and heterogeneous graph-based inference, respectively. The results showed that the prediction performance of the two algorithms on HPO-based is better than that on DO-based networks/matrices. In addition, our method can predict 11 novel cancer-associated lncRNAs, which are supported by literature evidence.

Transplantation of insulin-producing cells differentiated from human periosteum-derived progenitor cells ameliorate hyperglycemia in diabetic mice.

BACKGROUND: Periosteum-derived progenitor cells (PDPCs) isolated from the adult periosteum can differentiate into several specific cell types. In this study, we examined the characteristics of human PDPCs and insulin-producing cells (IPCs) differentiated from PDPCs and their ability to ameliorate hyperglycemia when transplanted into streptozotocin-induced nonobese diabetic-severe combined immunodeficiency diabetic mice. METHODS: Periosteum-derived progenitor cells were isolated from patients, expanded in culture, and subjected to a three-step differentiation protocol to produce IPCs. The expression of immunogenic, pluripotent, and pancreatic markers was examined, and glucose-stimulated insulin release in vitro was also assessed. Insulin-producing cells that differentiated from PDPCs were transplanted under the kidney capsule of streptozotocin-induced diabetic mice, and glucose levels and glucose tolerance were measured. RESULTS: We found that PDPCs expressed the mesenchymal stem cell markers CD73, CD90, and CD105 and the pluripotent markers, octamer-binding transcription factor 4 and Nanog, but not sex-determining region Y-box 2 or Rex1. Periosteum-derived progenitor cells expressed human leukocyte antigen-ABC but did not express human leukocyte antigen-DR or the costimulatory molecules CD80 and CD86. Differentiated IPCs expressed pancreatic hormones (insulin, glucagon, somatostatin, and glucose transporter 2), hormone processing, and secretion molecules (prohormone convertase-1 and convertase-2, Kir6.2), and pancreatic transcription factors (neurogenin 3, pancreatic and duodenal homeobox 1, sex-determining region Y-box 17). When IPCs were stimulated with glucose in vitro, insulin secretion was elevated. Transplantation of IPCs under the kidney capsules of diabetic mice improved hyperglycemia and glucose tolerance. Human insulin was detected in the serum and kidney sections of mice transplanted with IPCs differentiated from PDPCs. CONCLUSION: These results suggest that IPCs differentiated from PDPCs might be an alternative source of ß cells for treating diabetes.

[Functions of lncRNA in development and diseases]. / Rôle des longs ARN non codants dans le développement normal et pathologique.

The transcription of essentially the entire eukaryotic genome generates a myriad of non-coding RNA species that show complex overlapping patterns of expression and regulation. In the last decade, several large scale genomic analyses have shed light on the widespread existence of long non-coding RNAs (lncRNAs) in mammals. Although the function of most lncRNAs remains unknown, many of them have been suggested to play important roles in the regulation of gene expression during normal development and diseases, including cancers. Indeed, functional studies have demonstrated that lncRNAs participate in various biological processes, including reprogramming of pluripotent stem cells, oncogenic progression and cell cycle regulation. In this review, we summarize recent findings about the biology of lncRNAs and their functions in normal and pathological development in mammals.

Differentiation potential and profile of nuclear receptor expression during expanded culture of human adipose tissue-derived stem cells reveals PPARγ as an important regulator of Oct4 expression.

Potential therapeutic use of human adipose tissue-derived stem cells (hADSCs) requires the production of large cell numbers by in vitro expansion. However, long-term in vitro culture is associated with reduced stem cell characteristics and differentiation capability. We investigated the proliferation rate and expression of p16(INK4a) mRNA, surface stem cell markers, and stem cell transcription factors. The proliferation rate decreased significantly as passages increased, and the expression of p16(INK4a) mRNA significantly increased. FACS analysis of CD73, CD90, and CD105 expression showed no significant difference among examined passages; however, the mRNA expression levels of pluripotent markers, Oct4 and Nanog, were significantly decreased at higher passages. At passages 12 and 20, there was decreased differentiation capability into insulin-producing cells, evidenced by significantly decreased expression of insulin and related ß cell markers. Adipogenic and osteogenic differentiation was also decreased at higher passages. We then analyzed the transcriptional expression profiles of 48 nuclear receptors at four different passages. We found that the expression of peroxisome proliferator-activated receptor γ (PPARγ) and thyroid hormone receptor TRß was significantly decreased at higher passages. Treatment with PPARγ activators or overexpression of PPARγ in hADSCs at passage 20 could recover Oct4 expression levels and increase Oct4 promoter activity. PPARγ inactivation by GW9662 inhibited the troglitazone-induced Oct4 mRNA expression. Furthermore, PPARγ overexpression in hADSC at passage 20 improved the differentiation potential to insulin-producing cells. In conclusion, we demonstrated that hADSCs undergo characteristic changes and reduction of differentiation capability during expanded culture in vitro, and revealed the role of PPARγ as one potential factor in the regulation of Oct4 expression during in vitro aging of hADSCs.